This project's primary goal is the development of diagnostic markers and molecular clues for the understanding of genetic diseases of the central nervous system. A major effort has been placed on the use of two-dimensional electrophoresis (2DE) to separate proteins from complex solutions coupled with the use of silver staining, autoradiography, and automated computer densitometry. We have been able to: identify primary mutational events, detect secondary effects of a primary mutation (quantitative alterations in eleven lymphocyte proteins in the Lesch-Nyhan syndrome), and discover polymorphisms in 2DE patterns of human lymphocyte proteins. The ability to observe multiple polymorphisms in a subset of lymphocyte proteins with 2DE raises the possibility that this technique may provide a powerful tool for human genetic linkage studies. Genetic modelling studies predict that 200 polymorphisms would provide a human genetic linkage map which will prove useful in disease studies. A large family with familial Alzheimer's disease will be studied with these methods. This study should provide for the identification of additional polymorphisms and may uncover disease trait specific markers.